Development of a Working Definition of Severe Von Willebrand Disease

Introduction: von Willebrand Disease (VWD) is a heterogeneous disorder resulting from abnormalities of quantity and function of von Willebrand factor (VWF). The primary symptom of bleeding may manifest in different degrees ranging from mild to severe. The diagnosis and management of severe patients presents with challenges and may require a unique approach that is supported by the ASH ISTH NBDF WFH 2021 guidelines on the management of von Willebrand disease in its recommendation which states “In patients with VWD with a history of severe and frequent bleeds, the guideline panel suggests using long-term prophylaxis rather than no prophylaxis.” Definitions and criteria identifying this group of severe patients vary, taking into account bleeding symptoms, functional level, diagnostic VWD classification, and genetic findings, without meeting any specific standard that would be ideal. This project seeks to establish a working definition of severe von Willebrand disease by consensus amongst a group of experts on VWD.

Method: A panel of experts were first identified. A total of 23 individuals were invited, with 17 experts agreeing to participate and contribute their opinion. The panel represented a diverse opinion with 14 residing in North America, 2 in Europe, and 1 in Asia, and consisted of 12 physicians, 4 doctoral experts, 4 patients or family members, and 2 with other fields of expertise. A modified Delphi method was selected to establish a consensus. Responses were shared with everyone, although those providing the responses were able to remain anonymous to the rest of the panel. Modification to the methodology included using electronically disseminated surveys to gather opinions in each round and to anonymously share everyone’s comments. An initial meeting occurred at the outset to establish the fields and identify the potential criterion within each field that would become the subject for questioning. Questionnaires probed criterion that potentially could be utilized in a definition from each of the fields of genetics, diagnostic classification, functional laboratory results, and clinical bleeding symptoms and a summary of the responses after each round was completed. Each round of question and answers were disseminated sequentially with the subsequent round narrowed and focused by the previous round. Each expert’s opinion was summarized to prevent it from interfering with the other expert’s opinion. A predefined criteria of 80% concurring opinions established a consensus.

Results: The first round established that 1) genetics alone is currently not enough to establish a patient as having severe disease, 2) no diagnostic classification of VWD was sufficient to determine severe disease and 3) any VWD type may be severe or be at risk for severe symptoms, responding most Type 3 VWD are severe (but not all), many Type 2 VWD are severe, and some Type 1 VWD are severe. A preliminary draft definition was created for the summary and a second-round questionnaire was dispersed to further refine it. The second and final round resulted in the following working definition of severe von Willebrand disease:

A. Anyone meeting the diagnostic classification for von Willebrand disease

AND

B. Any VWF antigen or activity:

1. Result <20% regardless of bleeding phenotype

Or

2. Result <30% with excessive bleeding symptoms including: a. Bleeding that resulted in hospitalization, required surgical procedure, red blood cell transfusion, Hemoglobin decrease >2g/dL, or b. Intracranial, intraspinal, pericardial, retroperitoneal, intramuscular bleeding with compartment syndrome, or c. Persistent or recurrent bleeding that is disruptive of work or school.

Conclusion: von Willebrand disease is a heterogeneous disorder in which management and treatment of the group of patients with severe disease requires a very different approach; however, no specific or uniform standards exist for defining this patient group. This project creates a working consensus definition of severe von Willebrand disease, being vetted by ISTH Scientific and Standardization Committee, which will allow for consistent identification and therefore improved and more effective care of this population.